Excitotoxicity 1043263 220962838 2008-06-22T12:28:57Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. '''Excitotoxicity''' is the pathological process by which [[neuron|nerve cells]] are damaged and killed by glutamate and similar substances. This occurs when [[cell surface receptor|receptors]] for the excitatory neurotransmitter [[glutamic acid|glutamate]] such as the [[NMDA receptor]] and [[AMPA receptor]] are overactivated. Excitotoxins like [[NMDA]] and [[kainic acid]] which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of [[calcium in biology|calcium]] ions<ref name="Manev">Manev H, Favaron M, Guidotti A, and Costa E. Delayed increase of Ca<sup>2+</sup> influx elicited by glutamate: role in neuronal death. ''Molecular Pharmacoloy.'' 1989 Jul;36(1):106-112. PMID 2568579. Retrieved on [[January 31]], [[2007]].</ref> (Ca<sup>2+</sup>) to enter the [[cell (biology)|cell]]. Ca<sup>2+</sup> influx into cells activates a number of enzymes, including [[phospholipase]]s, [[endonuclease]]s, and [[proteases]] such as [[calpain]]. These enzymes go on to damage cell structures such as components of the [[cytoskeleton]], [[cell membrane|membrane]], and DNA. Excitotoxicity may be involved in [[spinal cord injury]], [[stroke]], [[traumatic brain injury]] and [[neurodegenerative disease]]s of the [[central nervous system]] (CNS) such as [[Multiple sclerosis]], [[Alzheimer's disease]], [[Amyotrophic lateral sclerosis]] (ALS), [[Parkinson's disease]], and [[Huntington's disease]].<ref name="Kim">Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity. Chapter 1 in ''CNS Neuroproteciton''. Marcoux FW and Choi DW, editors. Springer, New York. 2002. Pages 3-36 </ref> Other common conditions that cause excessive glutamate concentrations around neurons are [[hypoglycemia]]<ref name="camacho">Camacho A and Massieu L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. ''Archives of Medical Research.'' 2006. 37(1): 11-18. PMID 16314180. Retrieved on [[January 31]], [[2007]].</ref> and ''[[status epilepticus]].''<ref name="Fujikawa ">Fujikawa DG. Prolonged seizures and cellular injury: understanding the connection. ''Epilepsy & Behavior''. 2005 Dec;7 Suppl 3:S3-11. Published online 2005 Nov 8. PMID 16278099. Retrieved on [[January 31]], [[2007]]. </ref> ==History== The negative effects of glutamate were first observed in 1954 by [[T. Hayashi]], a Japanese scientist who noted that direct application of glutamate to the [[Central nervous system|CNS]] caused [[seizure]] activity, though this report went unnoticed for several years. The toxicity of glutamate was then observed by [[D. R. Lucas]] and [[J. P. Newhouse]] in 1957 when the feeding of [[monosodium glutamate]] to newborn [[mouse|mice]] destroyed the neurons in the inner layers of the [[retina]].<ref name="Lucas">Lucas DR and Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. ''AMA Archives of Ophthalmology.'' 1957 Aug;58(2):193-201. PMID 13443577. Retrieved on [[January 31]], [[2007]].</ref> Later, in 1969, [[John Olney]] discovered the phenomenon wasn't restricted to the retina but occurred throughout the [[brain]] and coined the term excitotoxicity. He also assessed that [[cell death]] was restricted to [[postsynaptic]] neurons, that glutamate [[agonist]]s were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate [[Receptor antagonist|antagonist]]s could stop the neurotoxicity.<ref name="Olney">Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. ''Science'' 1969 May 9;164(880):719-21. PMID 5778021. Retrieved on [[January 31]], [[2007]].</ref> ==Pathophysiology== Excitotoxicity can occur from substances produced within the body ([[endogenous]] excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is paradoxically also the major excitatory neurotransmitter in the mammalian CNS.<ref name="Temple">Temple MD, O'Leary DM, and Faden AI. The role of glutamate receptors in the pathophysiology of traumatic central nervous system injury. Chapter 4 in ''Head Trauma: Basic, Preclinical, and Clinical Directions''. Miller LP and Hayes RL, editors. Co-edited by Newcomb JK. John Wiley and Sons, Inc. New York. 2001. Pages 87-113. </ref> During normal conditions, glutamate [[concentration]] can be increased up to 1[[molar concentration|mM]] in the [[synaptic cleft]], which is rapidly decreased in the lapse of milliseconds. When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called [[apoptosis]]. This pathologic phenomenon can also occur after [[brain injury]]. [[Brain trauma]] or [[stroke]] can cause [[ischemia]], in which [[blood]] flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and [[aspartate]] in the [[extracellular fluid]], causing cell death, which is aggravated by lack of [[oxygen]] and [[glucose]]. The [[biochemical cascade]] resulting from ischemia and involving excitotoxicity is called the [[ischemic cascade]]. Because of the events resulting from ischemia and glutamate receptor activation, a deep [[induced coma|chemical coma]] may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need of oxygen and glucose) and save energy to be used to remove glutamate [[active transport|actively]]. (It must be noted that the main aim in induced comas is to reduce the [[intracranial pressure]], not brain [[metabolism]]). One of the damaging results of excess calcium in the cytosol is the opening of the [[mitochondrial permeability transition]] pore, a pore in the membranes of [[mitochondria]] that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release proteins that can lead to [[apoptosis]]. The pore can also cause mitochondria to release more calcium. In addition, production of [[adenosine triphosphate]] (ATP) may be stopped, and [[ATP synthase]] may in fact begin [[hydrolysis|hydrolysing]] ATP instead of producing it.<ref name="Stavrovskaya">Stavrovskaya IG and Kristal BS. The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? ''Free Radical Biology and Medicine''. 2005. 38(6): 687-697. PMID 15721979. Retrieved on [[January 31]], [[2007]]. </ref> Inadequate [[adenosine triphosphate]] production resulting from brain trauma can eliminate [[electrochemical gradient]]s of certain ions. [[Glutamate transporter]]s require the maintenance of these ion gradients in order to remove glutamate from the extracellular space. The loss of ion gradients results not only in the halting of glutamate uptake, but also in the reversal of the transporters, causing them to release glutamate and aspartate into the [[extracellular]] space. This results in a buildup of glutamate and further damaging activation of glutamate receptors.<ref name="siegel">Siegel, G J, Agranoff, BW, Albers RW, Fisher SK, Uhler MD, editors. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=glutamate+transporter+AND+bnchm%5Bbook%5D+AND+160512%5Buid%5D&rid=bnchm.section.1137 ''Basic Neurochemistry: Molecular, Cellular, and Medical Aspects'' 6th ed]. Philadelphia: Lippincott, Williams & Wilkins. 1999. </ref> On the [[molecular biology|molecular]] level, calcium influx is not the only thing responsible for apoptosis induced by excitoxicity. Recently<ref name="Hardingham">Hardingham GE, Fukunaga Y, and Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. ''Nature Neuroscience.'' 2002 May;5(5):405-414. PMID 11953750. Retrieved on [[January 31]], [[2007]].</ref> it has been noted that extrasynaptic NMDA receptor activation, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activate a [[CREB]] ([[Cyclic adenosine monophosphate|cAMP]] response element binding [[protein]]) shut-off, which in turn, caused loss of [[mitochondrial membrane]] potential and apoptosis. On the other hand, activation of synaptic NMDA receptors only activated the CREB [[Metabolic pathway|pathway]] which activates [[BDNF]] (brain-derived neurotrophic factor), not activating apoptosis. ==Excitotoxins in food additives== The most well-known (to the general public) excitotoxic concern is the current [[Aspartame controversy|debate over aspartame]], also known as [[NutraSweet]], and [[monosodium glutamate]] (MSG). Approximately 40% of [[aspartame]] (by mass) is broken down into the amino acid [[aspartic acid]] (also known as aspartate), an excitotoxin. Because aspartame is [[metabolism|metabolized]] and absorbed very quickly (unlike aspartic acid-containing proteins in foods){{Fact|date=May 2008}}, it is known that aspartame could spike blood plasma levels of aspartate.<ref name="Stegink ">Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE. Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. ''Metabolism''. 1987 May;36(5):507-512. PMID 3574137. Retrieved on [[January 31]], [[2007]].</ref> Glutamate does not normally cross the [[blood-brain barrier]] in most parts of the brain without active uptake by [[transport protein|transporters]].<ref name="Smith00">{{cite journal | last =Smith | first =QR | authorlink = | coauthors = | title =Transport of glutamate and other amino acids at the blood-brain barrier | journal = The Journal of nutrition | volume =130 | issue = Supplement 4S| pages = 1016S–1022S| publisher =The American Society for Nutritional Sciences | date= 2000 | url =http://jn.nutrition.org/cgi/content/full/130/4/1016S | doi = | pmid =10736373 | accessdate =2007-01-31 }} </ref> Glutamate concentrations in the blood are normally higher than those in the [[extracellular space]] around brain cells.<ref name="Smith00"/> ==See also== *[[Neurotoxicity]] *[[Glutamate receptor]] *[[Glutamatergic system]] *[[Monosodium glutamate]] *[[Aspartame controversy]] *[[NMDA receptor antagonist]] *[[Glutamic acid]] *[[Soy lecithin]] ==Sources== * [[Eric R. Kandel|Kandel ER]], Schwartz JH, and Jessel TM. 2000. ''[[Principles of Neural Science]], 4th Edition'', Page 928, McGraw Hill * [[Russell Blaylock|Blaylock RL]]. 1996. ''Excitotoxins: The Taste That Kills'' Health Press, ISBN 0929173252 ==References== {{reflist|2}} ==External links== * Blaylock RL. 1996. [http://www.dorway.com/blayenn.html Excitotoxins, Neurodegeneration and Neurodevelopment] Describes the possible presence of excitotoxins in food additives. DORway.com. Retrieved on [[January 31]], [[2007]]. [[Category:Neurotrauma]] [[Category:Neurochemistry]] [[Category:Food safety]] [[es:Excitotoxicidad]] [[fr:Excitotoxicité]] [[pl:Ekscytotoksyczność]] [[sv:Excitotoxicitet]]